评估小气道功能障碍在控制良好的哮喘（ATLANTIS）患者恶化风险中的作用：一项观察性研究
2025/10/31
摘要
背景：近期研究表明，尽管有基于指南的标准治疗，但超过50%的哮喘成年哮喘控制仍然不足。小气道往往被低估为气道阻塞和炎症的主要部位。这可能与缺乏对脉冲振荡法等现有工具的评估有关，因此治疗不足可能是控制不足的原因。小气道功能障碍在哮喘控制良好的成年人中很常见，可能是未来恶化风险的重要生物标志物。
目的：本研究旨在调查哮喘控制良好的患者是否存在小气道功能障碍，若是，这是否是该人群未来病情恶化的危险因素。
方法：2014年6月30日至2017年3月3日，小气道与哮喘相关性的观察性评估（ATLANTIS）研究纳入了来自9个国家29个初级和专科诊所的773名18-65岁哮喘患者。受试者需在纳入研究前至少6个月被诊断为哮喘，诊断基于高反应性、支气管扩张剂可逆性或峰值呼气流量变异性。患者需处于哮喘稳定期，定义为在基线访视前8周无哮喘加重，并定期接受恒定剂量的哮喘治疗。研究中哮喘控制良好的患者定义为基线时哮喘控制问卷（ACQ-6）得分低于0.75。根据脉冲振荡参数预测值的偏差，小气道功能障碍被定义为R5-R20（5 Hz电阻减去20 Hz电阻）和AX（电抗面积）的Z评分大于1645，X5（5 Hz电抗）的Z得分小于-1.645，并进行了进一步分析，探索了严重的小气道功能障碍（Z评分为3或-3）。ATLANTIS已在ClinicalTrials.gov注册，注册号为NCT02123667。
结果：在773名患者中，772名患者接受了ACQ-6评估。在这些患者中，384名（50%）被归类为哮喘控制良好，304名有R5-R20脉冲振荡数据的患者中有108名（36%[95%CI 30-41]）存在小气道功能障碍，261名有AX数据的患者有89名（34%[28-42]），303名有X5数据的患者中共有79名（26%[21-31]）。在多变量分析中，我们发现R5-R20定义的小气道功能障碍与未来急性发作的风险增加有关，与年龄、性别、吸烟状况、全球哮喘倡议第4-5阶梯、既往急性发作、预测FEV1的百分比、残余体积与总肺容量的比率和外周血嗜酸性粒细胞计数无关（风险比2.26[95%CI 1.05-4.85]；p=0.038），而AX（2.07[0.91-4.70]；p=0.082）和X5（0.86[0.33-2.21]；p=0.75）与急性发作无关。对于严重的小气道疾病，R5-R20（风险比2.80[1.26-6.26]；p=0.012）和AX（2.51[1.04-6.04]；p=0.041）都成为未来恶化的独立预测因素，而X5仍然不显著（风险比0.99[0.29-3.32]；p=0.98）。
结论：本研究通过阐明，作为被低估的特征，小气道功能障碍是控制良好的哮喘成年人未来恶化的常见、敏感、早期独立的风险生物标志物。
Assessment of the role of small airway dysfunction in relation to exacerbation risk in patients with well controlled asthma (ATLANTIS): an observational study.
Galant SP, Kuks PJM, Kole TM, Kraft M, Siddiqui S, Fabbri LM, Beghé B, Rabe KF, Papi A, Brightling CE, Singh D, Kocks JWH, Franzini L, Vonk JM, Kerstjens HAM, Heijink IH, Pouwels SD, Slebos DJ, van den Berge M.
Abstract
BACKGROUND:Recent surveys suggest that asthma remains inadequately controlled in more than 50% of adults with asthma despite guideline-based standard therapy. Small airways are often under-recognised as major sites of airway obstruction and inflammation. This might be related to lack of assessment with current tools such as impulse oscillometry, and thus under-treatment might explain inadequate control. Small airway dysfunction, which is common in adults with well controlled asthma, might represent an important biomarker of future risk of exacerbations.
OBJECTIVE:We aimed to investigate whether small airway dysfunction is present in patients with well controlled asthma and, if so, whether it is a risk factor for future exacerbations in this population.
METHODS:The observational Assessment of Small Airways Involvement in Asthma (ATLANTIS) study included 773 extensively characterised patients with asthma aged 18-65 years from 29 primary and specialty clinics in nine countries from June 30, 2014, to March 3, 2017. Patients were required to be diagnosed with asthma at least 6 months before inclusion based on evidence of airway hyper-responsiveness, bronchodilator reversibility, or peak expiratory flow variability. Patients were required to have stable asthma, defined as no asthma exacerbations and regular asthma treatment at a consistent dose for 8 weeks before baseline visits. The current analysis included patients with well controlled asthma, defined as an Asthma Control Questionnaire (ACQ-6) score of less than 0·75 at baseline. Small airway dysfunction was defined, based on deviation from predicted values of impulse oscillometry parameters, as a Z score of more than 1·645 for R5-R20 (resistance at 5 Hz minus resistance at 20 Hz) and AX (area of reactance) and a Z score of less than -1·645 for X5 (reactance at 5 Hz), with additional analyses exploring severe small airway dysfunction (Z score of 3 or -3). ATLANTIS is registered with ClinicalTrials.gov, NCT02123667.
RESULTS:Of 773 patients, ACQ-6 assessments were available for 772 patients. Among these patients, 384 (50%) were classified as having well controlled asthma, and small airway dysfunction was present in 108 (36% [95% CI 30-41]) of 304 patients with impulse oscillometry data available for R5-R20, 89 (34% [28-42]) of 261 patients with data for AX, and 79 (26% [21-31]) of 303 patients with data for X5. In the multivariable analysis, we found that R5-R20-defined small airway dysfunction was associated with increased risk of future exacerbations, independent of age, sex, smoking status, Global Initiative for Asthma steps 4-5, previous exacerbations, percentage of predicted FEV1, ratio of residual volume to total lung capacity, and peripheral blood eosinophil count (hazard ratio [HR] 2·26 [95% CI 1·05-4·85]; p=0·038), whereas AX (2·07 [0·91-4·70]; p=0·082) and X5 (0·86 [0·33-2·21]; p=0·75) were not associated with exacerbations. For severe small airway disease, both R5-R20 (HR 2·80 [95% CI 1·26-6·26]; p=0·012) and AX (2·51 [1·04-6·04]; p=0·041) became independent predictors of future exacerbations, whereas X5 remained non-significant (0·99 [0·29-3·32]; p=0·98).
CONCLUSION:We have addressed an undervalued trait by showing that small airway dysfunction is a common, sensitive, early independent risk biomarker for future exacerbations in adults with well controlled asthma.
背景：近期研究表明，尽管有基于指南的标准治疗，但超过50%的哮喘成年哮喘控制仍然不足。小气道往往被低估为气道阻塞和炎症的主要部位。这可能与缺乏对脉冲振荡法等现有工具的评估有关，因此治疗不足可能是控制不足的原因。小气道功能障碍在哮喘控制良好的成年人中很常见，可能是未来恶化风险的重要生物标志物。
目的：本研究旨在调查哮喘控制良好的患者是否存在小气道功能障碍，若是，这是否是该人群未来病情恶化的危险因素。
方法：2014年6月30日至2017年3月3日，小气道与哮喘相关性的观察性评估（ATLANTIS）研究纳入了来自9个国家29个初级和专科诊所的773名18-65岁哮喘患者。受试者需在纳入研究前至少6个月被诊断为哮喘，诊断基于高反应性、支气管扩张剂可逆性或峰值呼气流量变异性。患者需处于哮喘稳定期，定义为在基线访视前8周无哮喘加重，并定期接受恒定剂量的哮喘治疗。研究中哮喘控制良好的患者定义为基线时哮喘控制问卷（ACQ-6）得分低于0.75。根据脉冲振荡参数预测值的偏差，小气道功能障碍被定义为R5-R20（5 Hz电阻减去20 Hz电阻）和AX（电抗面积）的Z评分大于1645，X5（5 Hz电抗）的Z得分小于-1.645，并进行了进一步分析，探索了严重的小气道功能障碍（Z评分为3或-3）。ATLANTIS已在ClinicalTrials.gov注册，注册号为NCT02123667。
结果：在773名患者中，772名患者接受了ACQ-6评估。在这些患者中，384名（50%）被归类为哮喘控制良好，304名有R5-R20脉冲振荡数据的患者中有108名（36%[95%CI 30-41]）存在小气道功能障碍，261名有AX数据的患者有89名（34%[28-42]），303名有X5数据的患者中共有79名（26%[21-31]）。在多变量分析中，我们发现R5-R20定义的小气道功能障碍与未来急性发作的风险增加有关，与年龄、性别、吸烟状况、全球哮喘倡议第4-5阶梯、既往急性发作、预测FEV1的百分比、残余体积与总肺容量的比率和外周血嗜酸性粒细胞计数无关（风险比2.26[95%CI 1.05-4.85]；p=0.038），而AX（2.07[0.91-4.70]；p=0.082）和X5（0.86[0.33-2.21]；p=0.75）与急性发作无关。对于严重的小气道疾病，R5-R20（风险比2.80[1.26-6.26]；p=0.012）和AX（2.51[1.04-6.04]；p=0.041）都成为未来恶化的独立预测因素，而X5仍然不显著（风险比0.99[0.29-3.32]；p=0.98）。
结论：本研究通过阐明，作为被低估的特征，小气道功能障碍是控制良好的哮喘成年人未来恶化的常见、敏感、早期独立的风险生物标志物。
（中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校）
（Lancet Respir Med. 2025 Sep 29:S2213-2600(25)00283-8. doi: 10.1016/S2213-2600(25)00283-8.）
Assessment of the role of small airway dysfunction in relation to exacerbation risk in patients with well controlled asthma (ATLANTIS): an observational study.
Galant SP, Kuks PJM, Kole TM, Kraft M, Siddiqui S, Fabbri LM, Beghé B, Rabe KF, Papi A, Brightling CE, Singh D, Kocks JWH, Franzini L, Vonk JM, Kerstjens HAM, Heijink IH, Pouwels SD, Slebos DJ, van den Berge M.
Abstract
BACKGROUND:Recent surveys suggest that asthma remains inadequately controlled in more than 50% of adults with asthma despite guideline-based standard therapy. Small airways are often under-recognised as major sites of airway obstruction and inflammation. This might be related to lack of assessment with current tools such as impulse oscillometry, and thus under-treatment might explain inadequate control. Small airway dysfunction, which is common in adults with well controlled asthma, might represent an important biomarker of future risk of exacerbations.
OBJECTIVE:We aimed to investigate whether small airway dysfunction is present in patients with well controlled asthma and, if so, whether it is a risk factor for future exacerbations in this population.
METHODS:The observational Assessment of Small Airways Involvement in Asthma (ATLANTIS) study included 773 extensively characterised patients with asthma aged 18-65 years from 29 primary and specialty clinics in nine countries from June 30, 2014, to March 3, 2017. Patients were required to be diagnosed with asthma at least 6 months before inclusion based on evidence of airway hyper-responsiveness, bronchodilator reversibility, or peak expiratory flow variability. Patients were required to have stable asthma, defined as no asthma exacerbations and regular asthma treatment at a consistent dose for 8 weeks before baseline visits. The current analysis included patients with well controlled asthma, defined as an Asthma Control Questionnaire (ACQ-6) score of less than 0·75 at baseline. Small airway dysfunction was defined, based on deviation from predicted values of impulse oscillometry parameters, as a Z score of more than 1·645 for R5-R20 (resistance at 5 Hz minus resistance at 20 Hz) and AX (area of reactance) and a Z score of less than -1·645 for X5 (reactance at 5 Hz), with additional analyses exploring severe small airway dysfunction (Z score of 3 or -3). ATLANTIS is registered with ClinicalTrials.gov, NCT02123667.
RESULTS:Of 773 patients, ACQ-6 assessments were available for 772 patients. Among these patients, 384 (50%) were classified as having well controlled asthma, and small airway dysfunction was present in 108 (36% [95% CI 30-41]) of 304 patients with impulse oscillometry data available for R5-R20, 89 (34% [28-42]) of 261 patients with data for AX, and 79 (26% [21-31]) of 303 patients with data for X5. In the multivariable analysis, we found that R5-R20-defined small airway dysfunction was associated with increased risk of future exacerbations, independent of age, sex, smoking status, Global Initiative for Asthma steps 4-5, previous exacerbations, percentage of predicted FEV1, ratio of residual volume to total lung capacity, and peripheral blood eosinophil count (hazard ratio [HR] 2·26 [95% CI 1·05-4·85]; p=0·038), whereas AX (2·07 [0·91-4·70]; p=0·082) and X5 (0·86 [0·33-2·21]; p=0·75) were not associated with exacerbations. For severe small airway disease, both R5-R20 (HR 2·80 [95% CI 1·26-6·26]; p=0·012) and AX (2·51 [1·04-6·04]; p=0·041) became independent predictors of future exacerbations, whereas X5 remained non-significant (0·99 [0·29-3·32]; p=0·98).
CONCLUSION:We have addressed an undervalued trait by showing that small airway dysfunction is a common, sensitive, early independent risk biomarker for future exacerbations in adults with well controlled asthma.
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